The term "aerosol compressed-gas packages" denotes compression-proof containers from which a mixture of liquefied propellant and active substance stored under pressure is released by actuation of a valve. They have been used for many years for very varied purposes. Compressed-gas packages for pharmaceuticals are described e.g. in Sucker, Fuchs und Speiser (editor), Pharmazeutische Technologie, Thieme, Stuttgart, 1991, pp. 673-688; furthermore, aerosols and compressed-gas packages are described in List, Arzneiformenlehre, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1985, pp. 8-18 and in Voigt, Lehrbuch der pharmazeutischen Technologie, VCh, Weinheim, 1987 on pages 427-436. This popular form of administration is discussed in detail by Thoma, Aerosole, Selbstverlag, Frankfurt am Main, 1979.
Aerosol compressed-gas packages are used with advantage in medicine when active substances are to be administered directly into the lung and deposited there. Their advantage relies on the fact that, when they are used, a cloud of extremely finely dispersed particles is produced which can be breathed in by the patient. As a consequence, there is a rapid effect in the area of action, i.e., the lung, which is of decisive importance for the therapy, e.g. of bronchial asthma. On the other hand, in the prevention of asthma attacks by means of prophylactically active substances, direct administration to the lung makes it possible to keep the dose low. This minimizes the occurrence of undesired side effects in comparison with administration via the gastrointestinal tract, e.g., swallowing a tablet.
Aerosol compressed-gas packages have therefore found broad acceptance in the therapy of respiratory-tract illnesses. They are simple, reliable and economical. Possible problems in the coordination of the inspiration of the patient and the release of a puff of aerosol can be avoided either by expansion chambers (spacers) inserted between the aerosol package and the mouth of the patient or by special constructions of the inhalators in which the inspiration of the patient actuates release of a puff of aerosol.
Aerosol compressed-gas packages also can be used as a nasal spray and a mouth spray for oral, lingual and buccal administration of active substances.
In the past, among others, CFC's (fluorinated, chlorinated hydrocarbons) were used as the propellant for controlled dosage aerosols. Examples of known propellants include the following fluorinated, chlorinated hydrocarbons and hydrocarbons which can be used as propellants: Pentane, n-butane, iso-butane, TG 11, TG 12, TG 21, TG 22, TG 23, TG 113, TG 114, TG 115, TG 142 b and TG C 318.
The type designation of fluorinated chlorinated hydrocarbons is derived from the following key system:
Number in unit place=number of fluorine atoms (F) PA0 Number in decimal place minus 1=number of hydrogen atoms(H) PA0 Number in hundred's place plus 1=number of carbon atoms (C) PA0 Number of the valences still free=number of chlorine atoms (C1)
Since the development of the ozone theory (postulated degradation of the stratospheric ozone by CFC's and other chlorine-containing organic compounds) a search has been conducted for liquid gases suitable as propellants which are neither combustible nor are capable of degrading ozone and, in addition, are not detrimental to health.
For some time, non-chlorinated fluorocarbons such as e.g. 1,1,1,2-tetrafluoroethane (TG 134a) and 2H-heptafluoropropane (TG 227) have been investigated. In addition to TG 134a and TG 227, TG 152a (difluoroethane, CH.sub.3 CHF.sub.2) TG 143a (trifluoroethane, CH.sub.3 CF.sub.3) and TG 161 (fluoroethane, CH.sub.3 CH.sub.2 F) could be mentioned.
However, a disadvantage of these propellants is the fact that suspension stabilizers and valve lubricants hitherto used are not sufficiently soluble in them. Thus, the use of TG 134a requires approximately 25% ethanol in order to sufficiently dissolve the sorbitan trioleate (Span.RTM.) previously used in aerosol suspensions (see EP 372,777 A 2). The following compounds can also be used by way of example: Polyvalent alcohols such as e.g. glycerol, esters such as e.g. ethyl acetate, ketones such as e.g. acetone and hydrocarbons such as e.g. hexane and heptane, pentane and also isopropanol.
Such a high concentration of alcohol is disadvantageous because the active substance in the suspension can dissolve, and there is a danger of particle growth when that occurs. If the active-substance particles grow during storage of such a suspension beyond a size of 10 .mu.m, the aerosol valve can become clogged. In addition, the effectiveness of the aerosol can diminish, because the active-substance particles are no longer capable of reaching the lower sections of the lungs, because of their size.
There is therefore an urgent need for substances which
are physiologically acceptable
are technologically suitable for stabilizing aerosol suspensions of TG 134a or TG 227 as well as improving the function of the metering valve,
are soluble in TG 134a or TG 227 with or without using very small amounts of other physiologically acceptable solutizers,
are acceptable to the taste.